Enhanced skin penetration system for improved topical delivery of drugs

ABSTRACT

The invention involves pharmaceutical compositions for topical application comprising: 
     (a) a safe and effective amount of a pharmaceutical active; and 
     (b) from about 0.05% to about 5% of a non-ionic polyacrylamide having a molecular wight of from about 1,000,000 to about 30,000,000.

This is a division of application Ser. No. 08/390,902, filed on Feb. 16,1995, which is a continuation of application Ser. No. 08/228,167, filedon Apr. 15, 1994, which is a continuation of application Ser. No.08/111,032 filed on Aug. 24, 1993, which is a continuation ofapplication Ser. No. 07/957,752, filed on Oct. 2, 1992, which is acontinuation of application Ser. No. 07/778,424, filed on Oct. 16, 1991all now abandoned.

TECHNICAL FIELD

The present invention relates to compositions for the topicaladministration of drugs, especially such compositions having enhancedpenetration of the drug through the skin.

BACKGROUND OF THE INVENTION

Because of the accessibility and large area of the skin, it has longbeen considered a promising route for the administration of drugs,whether dermal, regional, or systemic effects are desired.

The advantages of the topical route of drug administration include:avoidance of the risks and inconvenience of parenteral treatment;avoidance of the variable absorption and metabolism associated with oraltreatment; continuity of drug administration, permitting use ofpharmacologically active agents with short biological half-lives;potential reduction of gastrointestinal irritation in systemicadministration; and treatment of curtaneous manifestations of diseasesusually treated systemically.

However, the impermeability of skin is well-known, serving as a barrierto ingress of pathogens and toxic chemicals, and egress of physiologicfluids. This impermeability is the result of normal physiologic changesin developing skin. A typical cell in the epidermis is formed in thebasal layer. It typically takes approximately thirty days for a cell tomigrate from the basal layer of the epidermis to sloughing off anddiscarding at the outer layers of the stratum corneum. As the cellmigrates outward from the basal layer, it progressively keratinizesuntil it is relatively impermeable. The result is the stratum corneum,an extremely thin surface layer (10 microns) with substantial barrierproperties. The cell envelopes of the cells in the stratum corneum tendto be mainly polar lipids, such as ceramides, sterols, and fatty acidswhile the cytoplasm of stratum corneum cells remains polar and aqueous.Despite the close packing of the cells, some 15% of the stratum corneumis intercellular and, generally, lipid based. It is generally recognizedthat over the very short term, penetration occurs through the hairfollicles and the sebaceous apparatus; long-term penetration occursacross cells (non-polar route). Poor penetration of many drugs acrossthe epidermal lipid barrier has, until now, frustrated attempts todeliver clinically significant doses of many drugs by the topical route.

One route of internal delivery of drugs is by transdermaladministration. Transdermal administration of drugs can be used in manyinstances to achieve therapeutic levels of the drugs in the systemiccirculatory system, as well as for more localized internal dosing ofdrugs. Where such therapeutic levels of drugs can be achieved bytransdermal administration, several potential advantages exist overother routes of administration. Sustained systemic delivery of drugcontrolled at therapeutic but below toxic levels over long periods oftime with a single continuous application is often an advantage oftransdermal drug administration. Potential contamination of internaltissues with undesired foreign substances or microbes, often associatedwith parenteral administration of drugs, is avoided with transdermaldrug administration. Oral administration of many drugs is undesirable orunfeasible because the drug decomposes in the harsh environment of thegastrointestinal tract, lacks sufficient absorption from thegastrointestinal tract, or causes gastrointestinal upset or tissuedamage in the gastrointestinal tract. First-pass metabolism of orallyadministered drugs can increase the dosage required to achievetherapeutic levels and thereby increase undesirable side effects eitherfrom the primary drug or the metabolites. Maintenance of uniform,optimal systemic levels of drugs for long periods of time is oftendifficult through oral administration. Such problems can often bereduced or avoided by transdermal drug administration.

Despite the substantial potential advantages for transdermaladministration of drugs, relatively few drugs are so administered. Theskin is a formidable barrier to the passage of most drugs. It is oftennecessary to provide a composition containing a skin penetrationenhancing vehicle in order to provide sufficient transdermal penetrationof the drug to achieve therapeutic levels of the drug at the targetinternal tissue. A number of skin penetration enhancing vehicles fordrugs have been disclosed, including those in the following references:U.S. Pat. No. 3,536,816 issued to Kellner on Oct. 27, 1970; U.S. Pat.No. 4,006,218 issued to Sipos on Feb. 1, 1977; U.S. Pat. No. 4,124,720issued to Wenmaekers on Nov. 7, 1978; U.S. Pat. No. 4,126,681 issued toReller on Nov. 21, 1978; U.S. Pat. No. 4,299,826 issued to Luedders onNov. 10, 1981; U.S. Pat. No. 4,305,936 issued to Klein on Dec. 15, 1981;U.S. Pat. No. 4,309,414 issued to Inagi, Muramatsu & Nagai on Jan. 5,1982; U.S. Pat. No. 4,338,306 issued to Kitao & Nishimura on Jul. 6,1982; U.S. Pat. No. 4,442,090 issued to Kakeya, Kitao & Nishimura onApr. 10, 1984; U.S. Pat. No. 4,485,033 issued to Kitao & Nishimura onNov. 27, 1984; U.S. Pat. No. 4,537,776 issued to Cooper on Aug. 27,1985; U.S. Pat. No. 4,552,872 issued to Cooper, Loomans & Fawzi on Nov.12, 1985; U.S. Pat. No. 4,557,934 issued to Cooper on Dec. 10, 1985;U.S. Pat. No. 4,573,995 issued to Chen, Chun & Enscore on Mar. 4, 1986;U.S. Pat. No. 4,626,539 issued to Aungst & DiLuocio on Dec. 2, 1986;U.S. Pat. No. 4,637,930 issued to Konno, Kawata, Aruga, Sonobe & Mitomiissued Jan. 20, 1987; U.S. Pat. No. 4,695,465 issued to Kigasawa,Ohtani, Tanaka & Hayashida on Sep. 22, 1987; European Patent ApplicationNo. 0,043,738 of The Procter & Gamble Company in the names of Wickett,Cooper & Loomans, published on Jun. 13, 1982; European PatentApplication No. 0,095,813 of The Procter & Gamble Company in the name ofCooper, published Dec. 7, 1983; PCT International Patent Application No.WO 87/03490 of Key Pharmaceuticals, Inc. in the names of Bodor andLoftson, published on Jun. 18, 1987; Washitake, M., T. Anmo, I. Tanaka,T. Arita & M. Nakano, "Percutaneous Absorption of Drugs from OilyVehicles", Journal of Pharmaceutical Sciences, Vol. 64, No. 3 (March,1975), pp. 397-401; Shahi, V., & J. L. Zatz, "Effect of FormulationFactors on Penetration of Hydrocortisone through Mouse Skin", Journal ofPharmaceutical Sciences, Vol. 67, No. 6 (June, 1978), pp. 789-792;Cooper, E. R., "Increased Skin Permeability for Lipophilic Molecules",Journal of Pharmaceutical Sciences, Vol. 73, No. 8 (August, 1984), pp.1153-1156; Aungst, B. J., N. J. Rogers & E. Shefter, "Enhancement ofNaloxone Penetration through Human Skin In Vitro Using Fatty Acids,Fatty Alcohols, Surfactants, Sulfoxides and Amides", InternationalJournal of Pharmaceutics, Vol. 33 (1986), pp. 225-234; Green, P. G., &J. Hadgraft, "Facilitated Transfer of Cationic Drugs Across a LipoidalMembrane by Oleic Acid and Lauric Acid", International Journal ofPharmaceutics, Vol. 37 (July, 1987), pp. 251-255.

It is an object of the present invention to provide novel compositionsfor enhancing the skin penetration of drugs.

It is a further object of the present invention to provide suchcompositions which provide sufficient skin penetration enhancement toachieve therapeutic levels of the drugs in target internal tissues.

It is a further object of the present invention to provide suchcompositions with low dermal irritation, especially in compositionsrequiring a low pH.

It is a still further object of the present invention to provide suchcompositions having good stability and good cosmetics.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical compositions for topicalapplication having enhanced penetration through the skin comprising:

(a) a safe and effective amount of a pharmaceutical active; and

(b) from about 0.05% to about 20% of a non-ionic polyacrylamide having amolecular wight of from about 1,000,000 to about 30,000,000.

All concentrations and ratios herein are by weight of total compositionand all measurements are at 25° C., unless otherwise specified.

DETAILED DESCRIPTION OF THE INVENTION

The present invention involves compositions comprising certain specificnon-ionic polymers which may be applied topically to the skin and whichresult in improved transdermal penetration of the drugs through theskin. These compositions also have a high solvent tolerance, i.e., highlevel of solvents such as alcohol and other water-soluble componentswhich may be necessary to solubilize the active can be included in thecompositions.

Drug Active

The compositions of the present invention comprise a safe and effectiveamount of a drug active. The phrase "safe and effective amount", as usedherein, means an amount of a drug high enough to significantlypositively modify the condition to be treated, but low enough to avoidserious side effects (at a reasonable benefit/risk ratio), within thescope of sound medical judgement. A safe and effective amount of thedrug will vary with the specific drug, the ability of the composition topenetrate the drug through the skin, the amount of composition to beapplied, the particular condition being treated, the age and physicalcondition of the patient being treated, the severity of the condition,the duration of the treatment, the nature of concurrent therapy, andlike factors.

The drug compounds present in the compositions of the present inventionpreferably comprise from about 0.1% to about 20% by weight of thecompositions, more preferably from about 0.1% to about 10%, and mostpreferably from about 0.1% to about 5%. Mixtures of drug actives mayalso be used.

Useful drug actives in the compositions of the present invention includeanti-acne drugs. Anti-acne drugs preferred for use in the presentinvention include the keratolytics such as salicylcic acid, sulfur,lactic acid, glycolic, pyruvic acid, urea, resorcinol, andN-acetylcysteine; retinoids such as retinoic acid and its derivatives(e.g., cis and trans); antibiotics and antimicrobials such as benzoylperoxide, octopirox, erythromycin, tetracyclin, triclosan, azelaic acidand its derivatives, phenoxy ethanol and phenoxy proponol, ethylacetate,clindamycin and meclocycline; sebostats such as flavinoids; hydroxyacids; and bile salts such as scymnol sulfate and its derivatives,deoxycholate, and cholate.

Useful drug actives in the compositions of the present invention includenon-steroidal anti-inflammatory drugs (NSAIDS). The NSAIDS can beselected from the following categories: propionic acid derivatives;acetic acid derivatives; fenamic acid derivatives; biphenylcarboxylicacid derivatives; and oxicams. All of these NSAIDS are fully describedin the U.S. Pat. No. 4,985,459 to Sunshine et al., issued Jan. 15, 1991,incorporated by reference herein. Most preferred are the propionicNSAIDS including but not limited to aspirin, acetaminophen, ibuprofen,naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen,indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen andbucloxic acid. Also useful are the steroidal anti-inflammatory drugsincluding hydrocortisone and the like.

Useful drug actives in the compositions of the present invention includeantihistaminic drugs. Antihistaminic drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of chlorpheniramine, triprolidine,diphenhydramine, doxylamine, pyrilamine, phenindamine, promethazine,cyproheptadine, azatadine, clemastine, carbinoxamine, tripelennamine,terfenadine, dexchlorpheniramine, brompheniramine, chlorcyclizine,diphenylpyraline, pheniramine and phenyltoloxamine, and mixturesthereof.

Useful drug actives in the compositions of the present invention includeantitussive drugs. Antitussive drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of dextromethorphan, codeine,caramiphen and carbetapentane.

Useful drug actives in the compositions of the present invention includeantipruritic drugs. Antipruritic drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of methdilizine and trimeprazine.

Useful drug actives in the compositions of the present invention includeanticholinergic drugs. Anticholinergic drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of scopolamine, atropine, homatropine,levodopa, dicyclomine, hyoscyamine, procyclidine, trihexyphenidyl andethopropazine.

Useful drug actives in the compositions of the present invention includeanti-emetic and antinauseant drugs. Anti-emetic and antinauseant drugspreferred for inclusion in compositions of the present invention includepharmaceutically-acceptable salts of cyclizine, meclizine,chlorpromazine, buclizine, metoclopramide, prochlorperazine andtrimethobenzamide.

Useful drug actives in the compositions of the present invention includeanorexic drugs. Anorexic drugs preferred for inclusion in compositionsof the present invention include pharmaceutically-acceptable salts ofbenzphetamine, phentermine, chlorphentermine, fenfluramine,diethylpropion and phendimetrazine.

Useful drug actives in the compositions of the present invention includecentral stimulant drugs. Central stimulant drugs preferred for inclusionin compositions of the present invention includepharmaceutically-acceptable salts of amphetamine, methamphetamine,dextroamphetamine and methylphenidate.

Useful drug actives in the compositions of the present invention includeantiarrhythmic drugs. Antiarrhythmic drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of propranolol, procainamide,disopyramide, quinidine, encainide, flecanaide, mexiletine andtocainide. Other antiarrhythmic drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of the quinidine derivatives disclosedin U.S. Pat. No. 4,716,171 issued to Jarreau and Koenig on Dec. 29,1987, which is hereby incorporated herein in its entirety by reference.Highly preferred compounds included in this class includepharmaceutically-acceptable salts of 3S-hydroxy-10,11-dihydroquinidine,3R-hydroxy-10,11-dihydroquinidine,3R-hydroxy-O-acetyl-10,11-dihydroquinidine, and3S-hydroxy-O-acetyl-10,11-dihydroquinidine, especially3S-hydroxy-10,11-dihydroquinidine.

Useful drug actives in the compositions of the present invention includeβ-adrenergic blocker drugs. β-Adrenergic blocker drugs preferred forinclusion in compositions of the present invention includepharmaceutically-acceptable salts of metoprolol, acebutolol, betaxolol,labetalol and timolol. β-Adrenergic blocker drugs more preferred forinclusion in compositions of the present invention include metoprololtartrate, acebutolol hydrochloride, betaxolol hydrochloride, labetalolhydrochloride and timolol maleate.

Useful drug actives in the compositions of the present invention includecardiotonic drugs. Cardiotonic drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of milrinone, amrinone and dobutamine.Other cardiotonic drugs preferred for inclusion in compositions of thepresent invention include pharmaceutically-acceptable salts of 14-aminosteroid derivatives, some of which are disclosed in U.S. Pat. Nos.4,325,879, 4,552,868 and 4,584,289, issued to Jarreau and Koenig on Apr.20, 1982, Nov. 12, 1985 and Apr. 22, 1986, respectively, each of whichare hereby incorporated herein in their entirety by reference.

Useful drug actives in the compositions of the present invention includeantihypertensive drugs. Antihypertensive drugs preferred for inclusionin compositions of the present invention includepharmaceutically-acceptable salts of enalapril, clonidine, hydralazine,minoxidil (which is also a hair growth stimulator drug), guanadrel,guanethidine, guanfacine, mecamylamine, methyldopate, pargyline,phenoxybenzamine and prazosin.

Useful drug actives in the compositions of the present invention includediuretic drugs. Diuretic drugs preferred for inclusion in compositionsof the present invention include pharmaceutically-acceptable salts ofamiloride and hydrochlorothiazide. Diuretic drugs more preferred forinclusion in compositions of the present invention include amiloridehydrochloride.

Useful drug actives in the compositions of the present invention includevasodilator drugs. Vasodilator drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of diltazem, amiodarone, isoxsuprine,nylidrin, tolazoline and verapamil.

Useful drug actives in the compositions of the present invention includevasoconstrictor drugs. Vasoconstrictor drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of dihydroergotamine, ergotamine andmethysergide.

Useful drug actives in the compositions of the present inventionincludes anti-ulcer drugs. Anti-ulcer drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of ranitidine and cimetidine.

Useful drug actives in the compositions of the present invention includeinclude anesthetic drugs. Anesthetic drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of lidocaine, bupivacaine,chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine,dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine andphenol.

Useful drug actives in the compositions of the present invention includeantidepressant drugs. Antidepressant drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of imipramine, desipramine,amitriptyline, nortriptyline, protriptyline, doxepin, maprotiline,phenelzine, tranylcypromine, trazodone and trimipramine.

Useful drug actives in the compositions of the present invention includetranquilizer and sedative drugs. Tranquilizer and sedative drugspreferred for inclusion in compositions of the present invention includepharmaceutically-acceptable salts of chlordiazepoxide, benactyzine,benzquinamide, flurazepam, hydroxyzine, loxapine and promazine.

Useful drug actives in the compositions of the present invention includeantipsychotic drugs. Antipsychotic drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of chlorprothixene, fluphenazine,haloperidol, molindone, thioridazine and trifluoperazine.

Useful drug actives in the compositions of the present invention includeantimicrobial drugs (antibacterial, antifungal, antiprotozoal andantiviral drugs). Antimicrobial drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of β-lactam drugs, quinolone drugs,ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin,triclosan, doxycycline, capreomycin, chlorhexidine, chlortetracycline,oxytetracycline, clindamycin, ethambutol, metronidazole, pentamidine,gentamicin, kanamycin, lineomycin, methacycline, methenamine,minocycline, neomycin, netilmicin, paromomycin, streptomycin,tobramycin, miconazole and amanfadine. Antimicrobial drugs preferred forinclusion in compositions of the present invention include tetracyclinehydrochloride, erythromycin estolate, erythromycin stearate (salt),amikacin sulfate, doxycycline hydrochloride, capreomycin sulfate,chlorhexidine gluconate, chlorhexidine hydrochloride, chlortetracyclinehydrochloride, oxytetracycline hydrochloride, clindamycin hydrochloride,ethambutol hydrochloride, metronidazole hydrochloride, pentamidinehydrochloride, gentamicin sulfate, kanamycin sulfate, lineomycinhydrochloride, methacycline hydrochloride, methenamine hippurate,methenamine mandelate, minocycline hydrochloride, neomycin sulfate,netilmicin sulfate, paromomycin sulfate, streptomycin sulfate,tobramycin sulfate, miconazole hydrochloride, amanfadine hydrochloride,amanfadine sulfate, triclosan, octopirox, parachlorometa xylenol,nystatin, tolnaftate and clotrimazole.

Useful drug actives in the compositions of the present invention includeantineoplastic drugs. Antineoplastic drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of bleomycin, daunorubicin,doxorubicin, mechlorethamine, procarbazine, quinacrine, tamoxifen,vinblastine and vincristine.

Useful drug actives in the compositions of the present invention includeantimalarial drugs. Antimalarial drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of chloroquine, hydroxychloroquineprimaquine and quinine.

Useful drug actives in the compositions of the present invention includemuscle relaxant drugs. Muscle relaxant drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of cinnamedrine, cyclobenzaprine,flavoxate, orphenadrine, papaverine, mebeverine, idaverine, ritodrine,dephenoxylate, dantrolene and azumolene.

Useful drug actives in the compositions of the present invention includeantispasmodic drugs. Antispasmodic drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of the compounds disclosed in U.S.Pat. No. 3,856,825 issued to Wright, Burch and Goldenburg on Dec. 24,1974, which is hereby incorporated herein in its entirety by reference.

Useful drug actives in the compositions of the present invention includeantidiarrheal drugs. Antidiarrheal drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of loperamide.

Useful drug actives in the compositions of the present invention includebone-active drugs. Bone-active drugs preferred for inclusion incompositions of the present invention includepharmaceutically-acceptable salts of diphosphonate drug compounds andphosphonoalkylphosphinate drug compounds, including the prodrug estersthereof. Such compounds are disclosed, for example, in U.S. Pat. Nos.3,683,080 issued to Francis on Aug. 8, 1972; 4,304,734 issued to Jary,Rihakova & Zobacova on Dec. 8, 1981; 4,687,768 issued to Benedict &Johnson on Aug. 18, 1987; 4,711,880 issued to Stahl & Schmitz on Dec. 8,1987; and 4,719,203 issued to Bosies & Gall on Jan. 12, 1988; copendingU.S. patent application Ser. Nos. 808,584, of Benedict & Perkins filedDec. 13, 1985; 945,069 of Ebetino, Buckingham & McOsker filed Dec. 19,1986; 945,068 of Ebetino & Benedict filed Dec. 19, 1986; and 069,666 ofEbetino filed Jul. 6, 1987; and European Patent Application Nos.0,001,584 of Blum, Hempel & Worms, published May 2, 1979; 0,039,033published Apr. 11, 1981; 0,186,405 of Benedict & Perkins, published Jul.2, 1986; and 0,243,173 of Oku, Todo, Kasahara, Nakamura, Kayakiri &Hashimoto, published Oct. 28, 1987; all of which are hereby incorporatedherein in their entirety by reference.

Also useful in the present invention are sunless tanning agentsincluding dihydroxyacetone, indole derivatives, and the like. Thesesunless tanning agents may also be used in combination with conventionalsunscreen agents such as those disclosed in Segarin, et al., at ChapterVIII, pages 189 et seq., of Cosmetics Science and Technology,incorporated by reference herein, as well as wound healing agents suchas peptide derivatives, yeast, panthenol, lamin and kinetin.

Other usefulskin actives include skin bleaching (or lightening) agentsincluding but not limited to hydroquinone, ascorbic acid, kojic acid andsodium metabisulfite.

Nonionic Polyacrylamide The non-ionic polymers useful in the presentinvention are polyacrylamides and substituted polyacrylamides, branchedor unbranched. These polymers are non-ionic water-dispersable polymerswhich can be formed from a variety of monomers including acrylamide andmethacrylamide which are unsubstituted or substituted with one or twoalkyl groups (preferably C₁ -C₅). Preferred acrylate amides andmethacrylate amides in which the amide nitrogen is unsubstituted, orsubstituted with one or two C₁ -C₅ alkyl groups (preferably: methyl,ethyl or propyl), for example, acrylamide, methacrylamide,N-methylacrylamide, N-methylmethacrylamide, N,N-dimethylmethacrylamide,N-isopropylacrylamide, N-isopropylmethacrylamide andN,N-dimethylacrylamide. These monomers are generally disclosed in U. S.Pat. No. 4,963,348 to Bolich, Jr. et al., issued Oct. 16, 1990,incorporated by reference herein in its entirety. These copolymers mayoptionally be formed using conventional neutral crosslinking agents suchas dialkenyl compounds. The use of such crosslinking agents for cationicpolymers is disclosed in U.S. Pat. No. 4,628,078 to Glover et al. issuedDec. 9, 1986 and U.S. Pat. No. 4,599,379 to Flesher et al. issued Jul.8, 1986 both of which are incorporated by reference herein. Thesenon-ionic co-polymers have a molecular weight greater than about1,000,000 preferably greater than about 1,500,000 and range up to about30,000,000. Preferably, as a result of being synthesized by reversephase emulsion polymerization, these non-ionic polyacrylamides arepredispersed in a water-immiscible solvent such as mineral oil and thelike, containing a high HLB surfactant (HLB from about 7 to about 10)which helps to facilitate water dispersibility of the polyacrylamide.Most preferred for use herein is the non-ionic polymer under the CTFAdesignation: polyacrylamide and isoparrafin and laureth-7, available asSepigel from Seppic Corporation.

These non-ionic polyacrylamides are present at a level from about 0.05%to about 20%, preferably from about 0.05% to 5% and most preferably fromabout 0.1% to about 10%.

Vehicle The compositions of the present invention are used along withpharmaceutically-acceptable carrier (or vehicle) components. The term"pharmaceutically-acceptable carrier components", as used herein, meanscompatible solid or liquid filler diluents which are suitable foradministration to a human or lower animal. The term "compatible", asused herein, means that the components are capable of being commingledwith the drug compounds, diols and fatty acids of the compositions ofthe present invention, and with each other, in a manner such that thereis no interaction which would substantially reduce the pharmaceuticalefficacy of the compositions of the present invention under ordinary usesituations. Pharmaceutically-acceptable carrier components must, ofcourse, be of sufficiently high purity and sufficiently low toxicity torender them suitable for administration to the human or lower animalbeing treated.

Some examples of substances which can serve aspharmaceutically-acceptable carrier components are polyethylene glycol;glycerol; ethanol; water; antioxidants; surfactants; chelating agents;preservatives; thickeners; as well as other non-toxic compatiblesubstances used in pharmaceutical formulations.

These compositions can also contain one or more humectants/moisturizersmany of which may also be useful as pharmaceutical actives. A variety ofhumectants/moisturizers can be employed and can be present at a level offrom about 1% to about 30%, more preferably from about 2% to about 8%and most preferably from about 3% to about 5%. These materials includepolyhydroxy alcohols such as sorbitol, glycerin, hexanetriol, propyleneglycol, hexylene glycol and the like; polyethylene glycol; sugars andstarches; sugar and starch derivatives (e.g. alkoxylated glucose);D-panthenol; hyaluronic acid; lactamide monoethanolamine; acetamidemonoethanolamine; and mixtures thereof.

Preferred humectants/moisturizers for use in the compositions of thepresent invention are the C₃ -C₆ diols and triols. Especially preferredis the triol, glycerin. The compositions of this invention may alsocontain pharmaceutically acceptable optional components that modify thephysical and/or therapeutic effects of the compositions. Such optionalcomponents may include, for example, additional solvents, emulsifiers,gelling agents, fragrances, preservatives, and stabilizers. However,such optional materials must not unduly interfere with the transdermaldelivery of the drug active. Optional components useful in thecompositions of this invention are described in the following patentdocuments, incorporated by reference herein: European Patent Publication43,738, Wickett et al., published Jan. 13, 1982; and U.S. Pat. No.4,552,872, Cooper et al., issued Nov. 12, 1985.

Most preferred compositions herein are gel-type compositions.

Another optional material is a solvent or co-solvent material. Suchsolvent materials include, for example, short chain alcohols and ethers.Preferred optional solvent materials include polyethylene glycols,dipropylene glycol, ethylene glycol monoethyl ether, ethanol,isopropanol, and dimethyl isosorbide. Water may also be used as asolvent or co-solvent in the compositions of this invention. If water isused in a saturated system, a gel or emulsion is preferably formed.

Most preferred compositions have a pH of below about 5, preferably belowabout 4, and most preferably below about 3.

While particular embodiments of the present invention have beendescribed, it will be obvious to those skilled in the art that variouschanges and modifications to the compositions disclosed herein can bemade without departing from the spirit and the scope of the invention.It is intended to cover, in the appended claims, all such modificationsthat are within the scope of this invention.

Test Method

Transdermal penetration of drugs is conveniently determined and comparedfrom various vehicles using the apparatus and procedure described below.

Full thickness excised human thigh skin is obtained from cadavers afterall hair had been clipped and the skin washed. The skin samples are thenbathed in 10% glycerin and stored frozen. The glycerin prevents theformation of ice crystals which could possibly damage the keratinizedcells and/or the intercellular lipid matrix. After a rapid thawing, theskin is conditioned for 24 hours in Hank's Balanced Salt Solution with1% antibacterial-antimycotic solution. Then the skin is washed withdistilled water. A single skin donor is used for each experiment, andindividual sections for use are selected based on integrity of thestratum corneum (visual determination). Selected areas are cut to 1 cm²using a scalpel.

Tests are conducted using glass diffusion cells placed intemperature-regulated stirring modules. Skin sections are mounted in thecells, and the receptor phase is added. The receptor phase is 50% Hank'sBalance Salt Solution with 1% antibiotic-antimycotic solution. Eachdiffusion cell has an exposed area of 0.79 cm² and a receptor capacityof 5 ml. Sufficient formulation is applied (750 ul) to the surface ofthe skin to ensure infinite dose conditions, and the diffusion cell iscovered with plastic wrap or parafilm to prevent product evaporation. Ateach sampling time the receptor phase is removed for analysis of drugcontent. The receptor phase is removed for analysis of drug content. Thereceptor phase is replenished at each sampling time in order to maintainsink conditions. Preferably 3 to 6 replicates are run with samplingintervals occurring at 1, 2, 4 & 6 hours.

Penetration rate (Flux) is determined as the quantity of drugpenetrating a measured area of skin per hour during the 5 hour intervalbetween 1 hour and 6 hours. Generally steady state is reached before 1hour. Penetration rate is usually expressed as ug drug per cm² skin perhour.

The following examples further describe and demonstrate embodimentswithin the scope of the present invention. The examples are given solelyfor the purpose of illustration and are not to be construed aslimitations of the present invention, as many variations thereof arepossible without departing from the spirit and scope of the invention.

Ingredients are identified by chemical or CTFA name.

EXAMPLES Example I

An anti-acne composition is made by combining the following ingredients.

    ______________________________________                                        Ingredient          (% W/W)                                                   ______________________________________                                        Water, Purified     52.395                                                    Alcohol SDA 40      40.000                                                    Polyacrylamide and  4.000                                                     C.sub.13-14 Isoparaffin and Laureth-7                                         Salicylic Acid      2.000                                                     Glycerin            1.000                                                     Aloe Vera Gel       0.500                                                     Menthol             0.100                                                     Disodium EDTA       0.005                                                     ______________________________________                                    

The alcohol is added to a suitable size container. Using a Lightnin'mixer with a 3 blade paddle prop, the salicylic acid is added to thealcohol and mixed at low speed (100 rpm) until the salicylic acid isdissolved. Menthol is added to the alcohol and mixed until dissolved.Separately, water is added to a suitable size container. Aloe vera geland disodium EDTA are added to the water and mixed at low speed (100rpm) until completely dissolved. The water phase is then added to thealcohol phase and mixed until clear. Gylcerin is added and mixed untilclear. While mixing at moderate speed (300 rpm), the polyacrylamide andC₁₃₋₁₄ isoparaffin and laureth-7 is added to form a gel. The resultinggel is mixed at moderate speed until uniform.

Example II

An anti-acne and/or analgesic composition is made by combining thefollowing ingredients utilizing conventional mixing techniques asdescribed above in Example I.

    ______________________________________                                        Ingredient          (% W/W)                                                   ______________________________________                                        Water, Purified     55.0                                                      Ibuprofen           2.0                                                       Alcohol SDA 40      40.0                                                      Polyacrylamide and  3.0                                                       C.sub.13-14 Isoparaffin and Laureth-7                                         ______________________________________                                    

The compositions display skin penetration of the Ibuprofen active aswell as improved skin feel and residue characteristics together withexcellent moisturizing, emolliency, rub-in and absorptioncharacteristics.

Example III

A keratolytic composition for dermatological disorders is made bycombining the following ingredients utilizing conventional mixingtechniques as described above in Example I.

    ______________________________________                                        Ingredient          (% W/W)                                                   ______________________________________                                        Water               86.5                                                      Urea                10.0                                                      Benzyl Alcohol      0.5                                                       Polyacrylamide and  3.0                                                       C.sub.13-14 Isoparaffin and Laureth-7                                         ______________________________________                                    

The compositions display skin penetration of the Urea active as well asimproved skin feel and residue characteristics together with excellentmoisturizing, emolliency, rub-in and absorption characteristics.

Example IV

A composition for sunless tanning is made by combining the followingingredients utilizing conventional mixing techniques as described abovein Example I.

    ______________________________________                                        Ingredient          (% W/W)                                                   ______________________________________                                        Water               91.5                                                      Benzyl Alcohol      0.5                                                       Polyacrylamide and  3.0                                                       C.sub.13-14 Isoparaffin and Laureth-7                                         Dihydroxyacetyone   3.0                                                       Glycerin            2.0                                                       ______________________________________                                    

The compositions display improved skin penetration of thedihydroxyacetone as well as improved skin feel and residuecharacteristics together with excellent moisturizing, emolliency, rub-inand absorption characteristics.

What is claimed is:
 1. A topical pharmaceutical composition havingenhanced penetration through he skin, comprising:(a) an aqueous carriercomprising from about 53% to about 91.5% water; (b) a safe and effectiveamount of an antimicrobial pharmaceutical active selected from the groupconsisting of β-lactam drugs, quinolone drugs, ciprofloxacin,norfloxacin, tetracycline, erythromycin, amikacin, triclosan,doxycycline, capremycin, chlorhexidine, chlortetracycline,oxytetracycline, clindamycin, ethambutol, metronidazole, pentamidine,gentamicin, kanamycin, lineomycin, methacycline, methenamine,minocycline, neomycin, netilmicin, paromomycin, streptomycin,tobramycin, miconazole, amanfadine, triclosan, octopirox, parachlorometaxylenol, nystatin, tolnaftate, clotrimazole, pharmaeutically-acceptablesalts thereof, and mixtures thereof; and (c) from about 0.05% to about5% of a non-ionic polyacrylamide having a molecular weight of from about1,000,000 to about 30,000,000, the polyacrylamide being predispersed ina water-immiscible oil containing a surfactant having an HLB of fromabout 7 to about 10,wherein the composition is in gel emulsion form andhas a pH below about
 5. 2. The composition of claim 1 wherein thepolyacrylamide comprises monomers selected from acrylamide andmethacrylamide which are unsubstituted or substituted with at least onealkyl group having from about 1 to about 5 carbon atoms.
 3. Thecomposition of claim 2 wherein the polyacrylamide comprises monomersselected from the group consisting of acrylamide, methacrylamide,N-methylacrylamide, N-methylmethacrylamide, N,N-dimethylmethacrylamide,N-isopropylacrylamide, N-isopropylmethacrylamide andN,N-dimethylacrylamide.
 4. The composition of claim 3 wherein thepolyacrylamide has a molecular weight greater than about 1,500,000. 5.The composition of claim 1 wherein said antimicrobial pharmaceuticalactive is selected from the group consisting of β-lactam drugs,quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin,amikacin, triclosan, doxycycline, capremycin, chlorhexidine,chlortetracycline, oxytetracycline, clindamycin, ethambutol,metronidazole, pentamidine, gentamicin, kanamycin, lineomycin,methacycline, methenamine, minocycline, neomycin, netilmicin,paromomycin, streptomycin, tobramycin, miconazole and amanfadine,pharmaceutically-acceptable salts thereof and mixtures thereof.
 6. Thecomposition of claim 1, comprising from about 0.1% to about 5% of thepolyacryamide.
 7. The composition of claim 1, comprising from about 0.1%to about 10% of the antimicrobial pharmaceutical active.
 8. Thecomposition of claim 1, comprising from about 0.1% to about 5% of theantimicrobial pharmaceutical active.
 9. The composition of claim 1,having a pH below about
 4. 10. The composition of claim 1, having a pHbelow about
 3. 11. The composition of claim 1, wherein the aqueouscarrier further comprises polyethylene glycol, glycerol or ethanol. 12.The composition of claim 1, wherein the polyacrylamide is predispersedin isoparrafin and laureth-7.
 13. The composition of claim 1, whereinthe antimicrobial pharmaceutical active is selected from the groupconsisting of tetracycline hydrochloride, erythromycin estolate,erythromycin stearate salt, amikacin sulfate, doxycycline hydrochloride,capreomycin sulfate, chlorhexidine gluconate, chlorhexidinehydrochloride, chlortetracycline hydrochloride, oxytetracyclinehydrochloride, clindamycin hydrochloride, ethambutol hydrochloride,metronidazole hydrochloride, pentamidine hydrochloride, gentamicinsulfate, kanamycin sulfate, lineomycin hydrochloride, methacyclinehydrochloride, methenamine hippurate, methenamine mandelate, minocyclinehydrochloride, neomycin sulfate, netilmicin sulfate, paromomycinsulfate, streptomycin sulfate, tobramycin sulfate, miconazolehydrochloride, amanfadine hydrochloride, amanfadine sulfate, triclosan,octopirox, parachlorometa xylenol, nystatin, tolnaftate andclotrimazole.